Despite widespread recognition of pervasive patient safety problems in the U.S. health care system, research to develop feasible, scalable solutions has lagged, particularly in the ambulatory setting. The need for new approaches to improve safety is especially pressing in the care of ambulatory patients using high-risk immunosuppressive medications, as reports of preventable adverse events among this category of drugs have increased. To date, no studies have carefully defined the epidemiology of these safety risks. The proposed Advancing Safety Process Innovation Using Registries (ASPIRE) project will use advanced electronic health record (EHR) data analytics to define the magnitude of ambulatory patient safety errors and adverse events for patients receiving high risk medications (Aim 1). We will also characterize disparities in these risks across race/ethnicity, socioeconomic status, and medical complexity. Three categories of patient safety processes will be examined: 1) preventive practices that reduce adverse medication events, 2) safety monitoring for patients using high-risk immunosuppressive medications, and 3) management of abnormal results from medication toxicity monitoring. These findings will be used to inform the development of eMeasures, a new approach to quality measurement that uses automatically extracted EHR information to give clinicians and health systems information regarding specific patient safety problems (Aim 2). We will use eMeasurement standards, including the Quality Data Model (QDM), Health Quality Measures Format (HQMF) and other structured coded terminologies to develop, specify and test system-wide prototype eMeasures. HIT-solutions such as eMeasures that can be applied across EHR data repositories serve as a foundation for a continuous learning health care system, as envisioned by the Institute of Medicine. The work proposed here builds the groundwork for further testing and nationwide dissemination of eMeasures to monitor and improve safety for those using high-risk medications in the ambulatory setting.